Prostate cancer is the second leading cause of cancer death in American males, and there is an urgent need for noveltherapies to treat or prevent recurrent and metastatic disease. Prostate-specific membrane antigen (PSMA) is a well-characterized glycoprotein whose expression is largely restricted to epithelial cells. In normal tissues, PSMA exists as a splice variant that lacks the transmembrane domain and is thereby retained in the cytoplasm. But on tumor cells, PSMA is expressed at high levels as a type II membrane protein that has a large extracellular domain. This unique pattern of expression and processing makes PSMA a highly attractive target for immunotherapy. We propose the development of novel PSMA-based vaccine therapies for prostate cancer. We have developed two lead vaccine candidates: a traditional purified protein vaccine as well as a novel viral vector vaccine. This Phase I application describes the critical preclinical development activities required to optimally advance the vaccines into human clinical trials. These activities relate to production of the vaccines and their characterization both in vitro and in vivo. Vaccines that are shown to accurately mimic and induce immunity to tumor-associated PSMA in the best available animal model will then be tested individually and in novel prime-boost combinations in human prostate cancer patients in the Phase II project. PROPOSED COMMERCIAL APPLICATION: The overall goal of this proposal is to develop PSMA-based vaccine therapies with the potential to induce robust antitumor responses in man. The lead vaccines identified with this proposed research will be moved into clinical trials and, if effective in humans, will be manufactured for commercial sale for the treatment of prostate cancer. The market for a successful immunotherapy includes men who have or who are at risk for the development of recurrent or metastatic disease. This would include a significant fraction of individuals diagnosed with prostate cancer, or 179,000 individuals in the U.S. The ex-U.S. market is approximately equal in magnitude.